Oncostatin M induced α1-antitrypsin (AAT) gene expression in Hep G2 cells is mediated by a 3′ enhancer

Morgan, Kevin; Marsters, Peter; Morley, Stephen; Gent, Diana van; Hejazi, Ala; Backx, Matt; Thorpe, Emma R.K.; Kalsheker, Noor

doi:10.1042/bj20011312

Cited by 26 publications

(18 citation statements)

References 32 publications

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“…By the stimulation with HGF and/or OSM, hAE cells expressed α1AT more strongly. This phenomenon is similar to that reported for the hepatocyte (Guillen et al, 1996;Morgan et al, 2002). This result led us to expect that hAE cells produce α1AT.…”

Section: Human Ae Cells Express a Part Of Hepatocyte-related Genessupporting

confidence: 76%

Human Amniotic Epithelial Cells Possess Hepatocyte-like Characteristics and Functions

Takashima

Ise

Zhao

et al. 2004

Cell Struct. Funct.

134

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ABSTRACT. Hepatocyte transplantation is expected to become a novel method for treatment of liver disease. However, many questions remain regarding this approach, especially concerning donor cells. To evaluate whether human amniotic epithelial cells can be used as a cell source for hepatocyte transplantation, hepatic gene expression and functions of human amniotic epithelial cells were analyzed. Reverse transcription-polymerase chain reaction analysis demonstrated that human amniotic epithelial cells expressed albumin, α1-antitrypsin, and other hepatocyte-related genes. Cultivated human amniotic epithelial cells demonstrated albumin production, glycogen storage, and albumin secretion consistent with the hepatocyte gene expression profile. In organ culture, the amnion secreted 30-fold larger amounts of albumin than human amniotic epithelial cells in monolayer culture. Moreover, in organ culture the amnion also secreted α1-antitrypsin. Following transplantation into mice, the amnion survived and secreted albumin. These observations suggest that transplantation of human amniotic epithelial cells and/or amnion could be novel therapeutic strategy for treatment of hepatic diseases, including α1-antitrypsin deficiency.

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Section: Human Ae Cells Express a Part Of Hepatocyte-related Genessupporting

confidence: 76%

Human Amniotic Epithelial Cells Possess Hepatocyte-like Characteristics and Functions

Takashima

Ise

Zhao

et al. 2004

Cell Struct. Funct.

134

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“…Lipoproteins may have pathophysiologic importance in lung disease 82 ; differences in apolipoprotein B have been described in association with lung function and COPD 83,84 , and a recent study identified an association between SNPs near APOM , lung function, and emphysema 85 . Similarly, our GRAIL analysis suggested a role for oncostatin M and its receptor, which may be of interest in COPD and emphysema 86,87 . Additional studies will be needed to confirm these findings.…”

Section: Discussionsupporting

confidence: 54%

Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

Cho

McDonald

Zhou

et al. 2014

The Lancet Respiratory Medicine

304

307

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Background The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. Methods Genome-wide association analysis in COPDGene (non-Hispanic whites and African-Americans) was combined with existing data from the ECLIPSE, NETT/NAS, and GenKOLS (Norway) studies. Analyses were performed both using all moderate-to-severe cases and the subset of severe cases. Top loci not previously described as genome-wide significant were genotyped in the ICGN study, and results combined in a joint meta-analysis. Findings Analysis of a total of 6,633 moderate-to-severe cases and 5,704 controls confirmed association at three known loci: CHRNA3/CHRNA5/IREB2, FAM13A, and HHIP (10−12 < P < 10−14), and also showed significant evidence of association at a novel locus near RIN3 (overall P, including ICGN = 5•4×10−9). In the severe COPD analysis (n=3,497), the effects at two of three previously described loci were significantly stronger; we also identified two additional loci previously reported to affect gene expression of MMP12 and TGFB2 (overall P = 2•6x10−9 and 8•3×10−9). RIN3 and TGFB2 expression levels were reduced in a set of Lung Tissue Research Consortium COPD lung tissue samples compared with controls. Interpretation In a genome-wide study of COPD, we confirmed associations at three known loci and found additional genome-wide significant associations with moderate-to-severe COPD near RIN3 and with severe COPD near MMP12 and TGFB2. Genetic variants, apart from alpha-1 antitrypsin deficiency, increase the risk of COPD. Our analysis of severe COPD suggests additional genetic variants may be identified by focusing on this subgroup. Funding National Heart, Lung, and Blood Institute; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; US Department of Veterans Affairs.

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“…Specifically, in the liver AAT is mainly regulated by IL-6-like cytokines including OSM. This process is mediated by the interaction between the hepatocyte promoter of SERPINA1 and an OSM response element located at the 3′UTR of the AAT gene via the interaction of transcription factors like STAT3 [25]. We found that OSM significantly up-regulates AAT expression in MM and MZ organoids under undifferentiated and differentiated stages, whereas in ZZ organoids AAT was up-regulated only after differentiation.…”

Section: Discussionmentioning

confidence: 75%

Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

et al. 2019

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Background and aims Alpha-1 antitrypsin (AAT) is a product of SERPINA1 gene mainly expressed by hepatocytes. Clinically relevant mutations in the SERPINA1 gene, such as Z (Glu342Lys), results in an expression of misfolded AAT protein having high propensity to polymerize, accumulate in hepatocytes and thus to enhance a risk for hepatocyte damage and subsequent liver disease. So far, the relationship between the Z-AAT accumulation and liver cell damage remains not completely understood. We present three-dimensional organoid culture systems, as a novel tool for modeling Z-AAT-related liver diseases. Methods We have established liver organoids from liver biopsies of patients with homozygous (ZZ) and heterozygous (MZ) deficiency and normal (MM) genotypes of AAT. The features of these organoid models were characterized by analyzing AAT protein secretion and intracellular aggregation in MZ and ZZ genotypes as well as SERPINA1 expression in differentiated cultures. Results Transcriptional analysis of differentiated organoid cultures by RNA-Seq showed hepatocyte-specific gene expression profile. Genes, such as ALB, APOB, CYP3A4 and SERPINA1, were validated and confirmed through quantitative-PCR analysis. The organoids from MZ and ZZ cases showed intracellular aggregation and lower secretion of AAT protein, and lower expression of ALB and APOB, as typically seen in hepatocytes from Z-AAT deficiency patients. Furthermore, organoids responded to external stimulus. Treatment with oncostatin M, a well-known inducer of SERPINA1, increased expression of the full-length transcripts (AAT-1C) as well as the short transcript of AAT (AAT-ST1C4). Conclusions Liver organoid model recapitulates the key features of Z-AAT deficiency and provides a useful tool for disease modeling.

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Oncostatin M induced α1-antitrypsin (AAT) gene expression in Hep G2 cells is mediated by a 3′ enhancer

Cited by 26 publications

References 32 publications

Human Amniotic Epithelial Cells Possess Hepatocyte-like Characteristics and Functions

Human Amniotic Epithelial Cells Possess Hepatocyte-like Characteristics and Functions

Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

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